This invention relates to antagonists of adenosine (FIG. 1; review; Daly J, Bruns F, Snyder SH (1982)Life Sci 28 2083-2097), which is naturally occurring compound in life forms. Adenosine has been thought to regulate a broad range of biological processes as an extracellular regulating compound, functioning as a neurotransmitter or hormone (Bern RM, Rall TW, Rubio R(eds)(1983)Regulatory function of adenosine. Martinus Nijhoff, Boston, this a book available in the National Library of Medicine). For example, adenosine has been implicated in cardiovascular, fat cell metabolism and mental function. Adenosine is currently thought to act through interaction with the A2 adenosine receptor subtype, which mediates stimulation of cyclic AMP production by adenylyl cyclase, and/or through interaction with the A1 adenosine receptor subtype, which mediates inhibition of this enzyme (Londos C, Cooper DMF, Wolff J(1980) P.N.A.S. U.S.A. 27 2551-2554). The relative abundance of these receptors in any one tissue determines the effects of adenosine in that specific tissue.
Many of the currently available adenosine antagonists have been xanthines, including caffeine, 8-.rho.-(sulfophenyl)theophylline and xanthine amine congener. These compounds have been recognized as being not as potent and as highly selective for either A1 or A2 receptors as would be needed for targeted activity. As a result, the effects of these compounds can reflect inhibition of both A1 and A2 effects. It is clearly preferred to have therapeutics which are able to selectively block either one or the other receptor. Very highly selective antagonists or agonists of A1 or A2 receptors have not been established.
Another limitation with some of these compounds is that they are not sufficiently potent. For example, at required concentrations they can act as inhibitors of phosphodiesterase.